, 2008 and Kaeser et al., 2011). The central PDZ-domain of RIMs binds at least two proteins: ELKS (Ohtsuka et al., 2002 and Wang et al., 2002) and N- and P/Q-type but not L-type Ca2+ channels (Kaeser et al., 2011). The physiological importance of ELKS binding to RIMs is unclear since the synaptic function of ELKS remains enigmatic (see below). In contrast, the binding of the RIM PDZ-domain to Ca2+ channels

is essential for recruiting Ca2+ channels to active zones (Kaeser et al., 2011 and Han et al., 2011). Synapses expressing mutant RIM that lacks the PDZ-domain exhibit Selleck MEK inhibitor a selective loss of presynaptic Ca2+ channels, with a resulting shift in the Ca2+-dependence of release to a higher Ca2+-requirement and a desynchronization of release (Kaeser et al., 2011). In addition to binding directly to RIMs, Ca2+ channels are tethered to the active zone by binding to RIM-BPs which in turn bind to RIMs (Figure 2). Specifically, the SH3-domains of RIM-BPs interact with proline-rich sequences of RIMs (localized between

this website their C2A and C2B domains) and of Ca2+ channels (in their cytoplasmic tails). A RIM fragment consisting of only its PDZ domain and proline-rich sequence is sufficient to rescue the presynaptic loss of Ca2+ channels in RIM-deficient synapses (Kaeser et al., 2011). Together, these data suggest that Ca2+ channels are recruited to active zones by a tripartite complex composed of RIMs, RIM-BPs, and the C-terminal tails of the channels (Figure 3). The function of the RIM C2 domains remains poorly

understood. The C2B domain binds to α-liprins and synaptotagmin-1 (Schoch et al., 2002), and the C2A domain may bind to SNARE proteins (Coppola et al., 2001), but it is unclear whether these interactions are physiologically relevant. The C2 domains may also bind to Ca2+ channels (Coppola et al., 2001), and the C2B domain of RIMs modulates Ca2+ channel opening (Uriu et al., 2010 and Kaeser et al., 2012). A fragment containing only the C2A and C2B domains of RIM partly rescues the decrease in synaptic strength observed in RIM-deficient synapses, without reversing the loss of presynaptic Ca2+ channels, suggesting that the C2 domains of RIM perform an active function in release (Kaeser et al., Edoxaban 2011). However, the nature of this function and its relation to the biochemical activities of the C2 domains remain unknown. RIM-BPs are large multidomain proteins (Figure 2). Vertebrates express three RIM-BP genes (Wang et al., 2000 and Mittelstaedt and Schoch, 2007), whereas Drosophila expresses only a single gene ( Liu et al., 2011). All RIM-BPs contain one central and two C-terminal SH3 domains and three central fibronectin III domains ( Wang et al., 2000 and Mittelstaedt and Schoch, 2007). The sequences separating these domains lack identifiable domains and vary among RIM-BP isoforms.